Human brain is a highly aerobic organ. With only five percent of the total body mass, it utilizes one fifth of the oxygen consumed by the entire body. Aerobic respiration is essential for providing the substantial energy needs of the normal brain activities in our daily life. Questions regarding the cerebral metabolic rate of oxygen consumption (CMRO2) are encountered frequently in biomedical research for understanding normal brain function and metabolic abnormalities associated with brain dysfunction and diseases. Modern neuroimaging techniques such as functional magnetic resonance (MR) imaging (fMRI) have revolutionized our ability to study brain function and human behavior. However, despite numerous research attempts and significant technology advances of the past three decades, current capability of neuroimaging approaches for accurate and noninvasive measurement of CMRO2 in human brain remains ultimately limited or problematic. To fill this technique gap, we have dedicated substantial efforts in recent years to develop and advance the high-field 17O-based MR spectroscopic imaging (MRSI) method for directly imaging CMRO2. This method relies on an inhalation of 17O-isotope-enriched oxygen gas, which is non-radioactive and stable, into the human body while monitoring the dynamic change of oxidative production of the 17O-labeled metabolic water in the brain using the 3D 17O MRSI. We have found that the 17O MR detection sensitivity increases almost quadratically with the magnetic field strength; and the feasibility, reliability and applicability of the 17O MR- based approach for noninvasively, quantitatively imaging CMRO2 at high/ultrahigh fields have been rigorously evaluated and verified in the animal models. Nevertheless, there are tremendous technical and methodological challenges to contend with before we can translate this 17O-based CMRO2 neuroimaging technology for biomedical applications in healthy humans and patients. In this grant application, we will address the most critical challenges with a number of innovative solutions and MR technologies aiming to rigorously validate and ultimately establish a rapid, accurate, cost-effective and completely noninvasive CMRO2 neuroimaging modality suitable for three-dimensional CMRO2 imaging of the entire human brain. The success of the proposed research will provide an important step towards closing the technology gap and making the novel CMRO2 neuroimaging tool available to a broad biomedical research community for studying the central roles of oxygen metabolism in the human brains under physiologic and pathologic conditions.